Mendelian randomization (MR) implemented through instrumental variables analysis is an increasingly popular causal inference tool used in genetic epidemiology. But it can have limitations for ...evaluating simultaneous causal relationships in complex data sets that include, for example, multiple genetic predictors and multiple potential risk factors associated with the same genetic variant. Here we use real and simulated data to investigate Bayesian network analysis (BN) with the incorporation of directed arcs, representing genetic anchors, as an alternative approach. A Bayesian network describes the conditional dependencies/independencies of variables using a graphical model (a directed acyclic graph) with an accompanying joint probability. In real data, we found BN could be used to infer simultaneous causal relationships that confirmed the individual causal relationships suggested by bi-directional MR, while allowing for the existence of potential horizontal pleiotropy (that would violate MR assumptions). In simulated data, BN with two directional anchors (mimicking genetic instruments) had greater power for a fixed type 1 error than bi-directional MR, while BN with a single directional anchor performed better than or as well as bi-directional MR. Both BN and MR could be adversely affected by violations of their underlying assumptions (such as genetic confounding due to unmeasured horizontal pleiotropy). BN with no directional anchor generated inference that was no better than by chance, emphasizing the importance of directional anchors in BN (as in MR). Under highly pleiotropic simulated scenarios, BN outperformed both MR (and its recent extensions) and two recently-proposed alternative approaches: a multi-SNP mediation intersection-union test (SMUT) and a latent causal variable (LCV) test. We conclude that BN incorporating genetic anchors is a useful complementary method to conventional MR for exploring causal relationships in complex data sets such as those generated from modern "omics" technologies.
Metabolomic profiling is a powerful approach to characterize human metabolism and help understand common disease risk. Although multiple high-throughput technologies have been developed to assay the ...human metabolome, no technique is capable of capturing the entire human metabolism. Large-scale metabolomics data are being generated in multiple cohorts, but the datasets are typically profiled using different metabolomics platforms. Here, we compared analyses across two of the most frequently used metabolomic platforms, Biocrates and Metabolon, with the aim of assessing how complimentary metabolite profiles are across platforms. We profiled serum samples from 1,001 twins using both targeted (Biocrates, n = 160 metabolites) and non-targeted (Metabolon, n = 488 metabolites) mass spectrometry platforms. We compared metabolite distributions and performed genome-wide association analyses to identify shared genetic influences on metabolites across platforms. Comparison of 43 metabolites named for the same compound on both platforms indicated strong positive correlations, with few exceptions. Genome-wide association scans with high-throughput metabolic profiles were performed for each dataset and identified genetic variants at 7 loci associated with 16 unique metabolites on both platforms. The 16 metabolites showed consistent genetic associations and appear to be robustly measured across platforms. These included both metabolites named for the same compound across platforms as well as unique metabolites, of which 2 (nonanoylcarnitine (C9) Biocrates/Unknown metabolite X-13431 Metabolon and PC aa C28:1 Biocrates/1-stearoylglycerol Metabolon) are likely to represent the same or related biochemical entities. The results demonstrate the complementary nature of both platforms, and can be informative for future studies of comparative and integrative metabolomics analyses in samples profiled on different platforms.
Since the discovery of stem cells and multipotency characteristics of mesenchymal stem cells (MSCs), there has been tremendous development in regenerative medicine. MSCs derived from bone marrow have ...been widely used in various research applications, yet there are limitations such as invasiveness of obtaining samples, low yield and proliferation rate, and questions regarding their practicality in clinical applications. Some have suggested that MSCs from other sources, specifically those derived from palatine tonsil tissues, that is, tonsil‐derived MSCs (TMSCs), could be considered as a new potential therapeutic tool in regenerative medicine due to their superior proliferation rate and differentiation capabilities with low immunogenicity and ease of obtaining. Several studies have determined that TMSCs have differentiation potential not only into the mesodermal lineage but also into the endodermal as well as ectodermal lineages, expanding their potential usage and placing them as an appealing option to consider for future studies in regenerative medicine. In this review, the differentiation capacities of TMSCs and their therapeutic competencies from past studies are addressed. Stem Cells 2019;37:1252–1260
Schematic illustration of lineage differentiation of tonsil‐derived mesenchymal stem cells.
Mammography screening has been proven to detect breast cancer at an early stage and reduce mortality; however, it has low accuracy in young women or women with dense breasts. Blood-based diagnostic ...tools may overcome the limitations of mammography. This study assessed the diagnostic performance of a three-protein signature in patients with suspicious breast lesions.
This trial (MAST; KCT0004847) was a prospective multicenter observational trial. Three-protein signature values were obtained using serum and plasma from women with suspicious lesions for breast malignancy before tumor biopsy. Additionally, blood samples from women who underwent clear or benign mammography were collected for the assays. Among 642 participants, the sensitivity, specificity, and overall accuracy values of the three-protein signature were 74.4%, 66.9%, and 70.6%, respectively, and the concordance index was 0.698 (95% CI 0.656, 0.739). The diagnostic performance was not affected by the demographic features, clinicopathologic characteristics, and co-morbidities of the participants.
The present trial showed an accuracy of 70.6% for the three-protein signature. Considering the value of blood-based biomarkers for the early detection of breast malignancies, further evaluation of this proteomic assay is warranted in larger, population-level trials. This Multi-protein Assessment using Serum to deTermine breast lesion malignancy (MAST) was registered at the Clinical Research Information Service of Korea with the identification number of KCT0004847 ( https://cris.nih.go.kr ).
Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of ...age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.
This study aimed to compare the mean scores of mobile phone use, mobile phone addiction, and depressive symptoms at three-time points among Korean adolescents according to gender and to examine the ...differences in the long-term relationships among the three abovementioned variables between Korean boys and girls in a four-year period. Data for 1794 adolescents (897 boys and 897 girls) were obtained from three waves of the second panel of the Korean Children and Youth Panel Survey. Multigroup structural equation modeling was used for data analyses. The study findings showed that at each of the three-time points, Korean girls tended to use their mobile phones more frequently and were at a higher risk of mobile phone addiction and depressive symptoms than Korean boys. Significant changes were observed in the longitudinal relationships among phone use, mobile phone addiction, and depressive symptoms in Korean adolescents across time periods, but no gender differences were found in the strengths of these relationships. These findings contribute to expanding the knowledge base of mobile phone addiction and depressive symptoms among Korean adolescents.
Acute hepatitis A (AHA) involves severe CD8+ T cell-mediated liver injury. Here we showed during AHA, CD8+ T cells specific to unrelated viruses became activated. Hepatitis A virus (HAV)-infected ...cells produced IL-15 that induced T cell receptor (TCR)-independent activation of memory CD8+ T cells. TCR-independent activation of non-HAV-specific CD8+ T cells were detected in patients, as indicated by NKG2D upregulation, a marker of TCR-independent T cell activation by IL-15. CD8+ T cells derived from AHA patients exerted innate-like cytotoxicity triggered by activating receptors NKG2D and NKp30 without TCR engagement. We demonstrated that the severity of liver injury in AHA patients correlated with the activation of HAV-unrelated virus-specific CD8+ T cells and the innate-like cytolytic activity of CD8+ T cells, but not the activation of HAV-specific T cells. Thus, host injury in AHA is associated with innate-like cytotoxicity of bystander-activated CD8+ T cells, a result with implications for acute viral diseases.
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•During acute hepatitis A (AHA), non-HAV-specific memory CD8+ T cells are activated•Non-HAV-specific CD8+ T cells are activated by IL-15 produced by HAV-infected cells•CD8+ T cells of AHA patients exert TCR-independent, innate-like cytotoxicity•Innate-like cytotoxicity of CD8+ T cells is associated with liver injury in AHA
During acute hepatitis A, hepatitis A virus (HAV)-infected cells produce IL-15 that induces TCR-independent bystander activation of non-HAV-specific memory CD8+ T cells. These CD8+ T cells exert innate-like cytotoxicity triggered by NKG2D and NKp30 without TCR engagement. The severity of liver injury is associated with activation and innate-like cytotoxicity of non-HAV-specific CD8+ T cells, but not the activation of HAV-specific T cells. Thus, IL-15-induced bystander-activated CD8+ T cells are implicated in host injury during acute viral infection.
Disease risk and incidence between males and females reveal differences, and sex is an important component of any investigation of the determinants of phenotypes or disease etiology. Further striking ...differences between men and women are known, for instance, at the metabolic level. The extent to which men and women vary at the level of the epigenome, however, is not well documented. DNA methylation is the best known epigenetic mechanism to date.
In order to shed light on epigenetic differences, we compared autosomal DNA methylation levels between men and women in blood in a large prospective European cohort of 1799 subjects, and replicated our findings in three independent European cohorts. We identified and validated 1184 CpG sites to be differentially methylated between men and women and observed that these CpG sites were distributed across all autosomes. We showed that some of the differentially methylated loci also exhibit differential gene expression between men and women. Finally, we found that the differentially methylated loci are enriched among imprinted genes, and that their genomic location in the genome is concentrated in CpG island shores.
Our epigenome-wide association study indicates that differences between men and women are so substantial that they should be considered in design and analyses of future studies.
Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of ...2,204 females (115 type 2 diabetic T2D case subjects, 192 individuals with impaired fasting glucose IFG, and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio OR 1.65 95% CI 1.39-1.95, P = 8.46 × 10(-9)) and was moderately heritable (h(2) = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 1.34-2.11, P = 6.52 × 10(-6)) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 1.27-2.75, P = 1 × 10(-3)). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.
Identification of specific needs in patients with cancer is very important for the provision of patient-centered medical service. The aim of this study was to investigate the unmet needs and related ...factors of Korean breast cancer survivors.
A multicenter, cross-sectional, interview survey was performed among 332 Korean breast cancer survivors. The Comprehensive Needs Assessment Tool for cancer patients was administered to survivors who gave written informed consent to participate. Data were analyzed using t-test, ANOVA and multiple regression analysis.
The level of unmet needs was highest in the domain 'Information and education' (mean ± SD; 1.70 ± 1.14) and the item with the highest level of unmet needs was 'Needed help in coping with fear of recurrence' (2.04 ± 1.09). Unmet needs were correlated with age, stage, multiplicity, HER2, treatment state, marital status, employment, psychosocial status, and problems in EQ-5D dimensions. In multiple regression analysis, the 50-59 age group showed a higher level of recognition for physical symptom needs and the unemployed group expressed greater needs for information and education. Survivors with multiplicity had greater needs in the domains of healthcare staff and physical symptom. The stress group showed high levels of needs in all domains except religious support. The group with thoughts of suicide showed higher levels of unmet needs for physical symptom.
Most prevalent unmet needs in Korean breast cancer survivors were found in the 'information and education' domain. The 50-59 age group, unemployment, multiplicity, stress and suicidal thoughts were associated with higher levels of unmet needs among Korean breast cancer survivors. Our findings revealed more vulnerable breast cancer survivors with unmet needs and physicians should take a precision approach to satisfy unmet needs of these survivors.
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